IL-17/Notch1/STAT3 Pathway Contributes to 5-Fluorouracil-Induced Intestinal Mucositis in Rats: Amelioration by Thymol Treatment.

5-Fluorouracil (5-FU) is an anticancer drug with intestinal mucositis (IM) as a deleterious side effect. Thymol is a monoterpene phenol which has been reported to possess an antioxidant and anti-inflammatory activity versus 5-FU-induced IM. The Notch pathway affects multiple cellular activities, such as cellular proliferation, in addition to inflammatory responses modulation. Accordingly, this work was carried out in order to elucidate the role of the Notch pathway in 5-FU-induced IM and to further elucidate the immunomodulatory protective mechanisms of thymol. Experimental rats were divided randomly into four groups: Control, 5-FU, 5-FU+thymol (60 mg/kg/day), and 5-FU+thymol (120 mg/kg/day). 5-FU was injected intraperitoneally at a dose of 150 mg/kg on days 6 and 7, while thymol was orally administered daily for 11 days. By the end of the study, intestinal tissues were collected for the determination of IL-17, CD4, CD8, Notch1, Hes-1, pSTAT3, and STAT-3 protein expressions. The effect of thymol on 5-FU cytotoxicity was also examined using WST1 assay. 5-FU induced a marked increase in IL-17 levels, along with a marked downregulation of CD4 and the upregulation of CD8, Notch1, Hes-1 protein expressions, and activation of STAT3 in the intestinal tissue when compared with the control group. Thymol ameliorated the changes that occurred in these parameters. Additionally, cytotoxicity testing revealed that thymol augmented the antiproliferative action of 5-FU against breast and colorectal human cancer cell lines. This study was the first to show that the IL-17/Notch1/STAT3 pathway is involved in the molecular mechanism of 5-FU-induced IM, as well as the immunomodulatory activity of thymol.

Liraglutide Effect on Weight, Glycated Hemoglobin, and Blood Pressure: A Single-Center Experience in the Eastern Province of Saudi Arabia.

Background Liraglutide has pleiotropic effects beneficial to patients with cardiovascular and renal risks. These effects have been linked to weight and blood pressure reduction in type 2 diabetes (T2D) patients. However, whether this reduction is similar in all patients regardless of their ethnicity, baseline demographic, or clinical characteristics is unknown. This study aimed to identify the efficacy of liraglutide on weight, glycated hemoglobin (HbA1c), and blood pressure in Saudi patients with T2D who attended King Fahad Hospital of the University and received liraglutide as add-on therapy to other antihyperglycemic agents. The study also aimed to describe the pattern of change in these clinical parameters before and after the treatment and assess whether sex differences affect liraglutide's efficacy. Methods We conducted a retrospective longitudinal study reviewing medical records of 220 Saudi patients with T2D treated at King Fahad Hospital of the University (KFHU), in Al-Khobar city in the Eastern Province of Saudi Arabia, from December 2016 to November 2021. Patient cases were included if the patient was Saudi, aged 18 or older, and received liraglutide in a dose of at least 0.6 mg/day for at least three months in combination with other antihyperglycemic agents/diabetes medications. We recorded the effect on patient HbA1c, systolic blood pressure (SBP) and diastolic blood pressure (DBP), body mass index (BMI), and body weight at baseline, during, and after treatment. We used the paired t-test and repeated measure analysis of variance to compare the mean study parameters before and after treatment. Furthermore, an independent t-test was used to compare the mean study parameters among men and women. Results Treatment with liraglutide from 0.6 mg/day to 3 mg/day for three to 18 months had optimal results across the outcomes measured in our cohort study. There was a significant reduction in weight from baseline to 18 months from a mean weight of 97.9±20 kg to 96.51±18.45 kg with (p<0.001). Mean HbA1c at baseline was 9.34%±1.95%, dropped to 7.67%±1.11% (p<0.001) at 18 months. Moreover, mean SBP also significantly decreased from 126.61±10.4 mmHg to 122.48±7.29 mmHg by the last follow-up (p<0.001). Mean DBP was 76.54±8.37 mmHg at baseline and decreased to 74.29±6.22 mmHg at last follow-up (p<0.001). Men treated with liraglutide had greater reductions in weight than women throughout the study (p<0.05), and while men had greater reductions in SBP and DBP than women early in treatment (p<0.05), by the end of treatment, there were no significant differences in blood pressure between men and women. Likewise, we saw no significant difference between HbA1c reductions in men and women treated with liraglutide. Conclusion Liraglutide effectively reduces HbA1c, weight, BMI, SBP, and DBP in T2D patients. These study results reflect real-world liraglutide clinical practices from KFHU and can be beneficial for physicians when considering using liraglutide as add-on therapy in this population.

Retraction: Liraglutide Effect on Weight, Glycated Hemoglobin, and Blood Pressure: A Single-Center Experience in the Eastern Province of Saudi Arabia.

[This retracts the article DOI: 10.7759/cureus.23554.].

Carvacrol and Thymol Modulate the Cross-Talk between TNF-α and IGF-1 Signaling in Radiotherapy-Induced Ovarian Failure.

Premature ovarian failure (POF) is a common cause of infertility in premenopausal women who are unavoidably exposed to cytotoxic therapy. Radiotherapy is one of the most effective cytotoxic treatments. However, the radiosensitivity of ovarian tissues limits its therapeutic outcome and results in the depletion of the primordial follicle and loss of fertility. Therefore, the need for an effective radioprotective therapy is evident especially when none of the current clinically used modalities for radioprotection succeeds efficiently. The present study investigated the potential radioprotective effect of carvacrol (CAR) (80 mg) or thymol (80 mg) on gamma- (γ-) irradiation-induced ovarian damage as well as their role in the cross-talk between IGF-1 and TNF-α signaling and antioxidative activity. In immature female Wister rats, a single dose of whole-body irradiation (3.2 Gy, LD20) produced considerable ovarian damage, which was evident by histopathological findings and hormonal changes. Interestingly, pretreatment with CAR or thymol significantly enhanced the follicular development and restored the anti-Mullerian hormone (AMH), E2, and FSH levels. Both essential oils improved the irradiation-mediated oxidative stress and reduction in proliferating cell nuclear antigen (PCNA) expression. Moreover, irradiated rats exhibited an inverse relationship between IGF-1 and TNF-α levels two days post irradiation, which was further inverted by the pretreatment with CAR and thymol and ought to contribute in their radioprotective mechanisms. In conclusion, CAR and thymol showed a radioprotective effect and rescued the ovarian reserve mainly through counteracting oxidative stress and the dysregulated cross-talk between IGF-1 and TNF-α.